TY - JOUR
T1 - Multispecies Evaluation of a Long-Acting Tenofovir Alafenamide Subdermal Implant for HIV Prophylaxis
AU - Gunawardana, Manjula
AU - Remedios-Chan, Mariana
AU - Sanchez, Debbie
AU - Webster, Simon
AU - Galvan, Patricia
AU - Fanter, Rob
AU - Castonguay, Amalia E.
AU - Webster, Paul
AU - Moss, John A.
AU - Kuo, Joseph
AU - Gallay, Philippe A.
AU - Vincent, Kathleen L.
AU - Motamedi, Massoud
AU - Weinberger, Dana
AU - Marzinke, Mark A.
AU - Hendrix, Craig W.
AU - Baum, Marc M.
N1 - Funding Information:
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI120748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The sheep study was carried out using internal, discretionary funds that are gratefully acknowledged.
Funding Information:
The authors thank Gilead Sciences, Inc. for providing TAF.
Publisher Copyright:
© Copyright © 2020 Gunawardana, Remedios-Chan, Sanchez, Webster, Galvan, Fanter, Castonguay, Webster, Moss, Kuo, Gallay, Vincent, Motamedi, Weinberger, Marzinke, Hendrix and Baum.
PY - 2020/11/25
Y1 - 2020/11/25
N2 - New HIV-1 infection rates far outpace the targets set by global health organizations, despite important progress in curbing the progression of the epidemic. Long-acting (LA) formulations delivering antiretroviral (ARV) agents for HIV-1 pre-exposure prophylaxis (PrEP) hold significant promise, potentially facilitating adherence due to reduced dosing frequency compared to oral regimens. We have developed a subdermal implant delivering the potent ARV drug tenofovir alafenamide that could provide protection from HIV-1 infection for 6 months, or longer. Implants from the same lot were investigated in mice and sheep for local safety and pharmacokinetics (PKs). Ours is the first report using these animal models to evaluate subdermal implants for HIV-1 PrEP. The devices appeared safe, and the plasma PKs as well as the drug and metabolite concentrations in dermal tissue adjacent to the implants were studied and contrasted in two models spanning the extremes of the body weight spectrum. Drug and drug metabolite concentrations in dermal tissue are key in assessing local exposure and any toxicity related to the active agent. Based on our analysis, both animal models were shown to hold significant promise in LA product development.
AB - New HIV-1 infection rates far outpace the targets set by global health organizations, despite important progress in curbing the progression of the epidemic. Long-acting (LA) formulations delivering antiretroviral (ARV) agents for HIV-1 pre-exposure prophylaxis (PrEP) hold significant promise, potentially facilitating adherence due to reduced dosing frequency compared to oral regimens. We have developed a subdermal implant delivering the potent ARV drug tenofovir alafenamide that could provide protection from HIV-1 infection for 6 months, or longer. Implants from the same lot were investigated in mice and sheep for local safety and pharmacokinetics (PKs). Ours is the first report using these animal models to evaluate subdermal implants for HIV-1 PrEP. The devices appeared safe, and the plasma PKs as well as the drug and metabolite concentrations in dermal tissue adjacent to the implants were studied and contrasted in two models spanning the extremes of the body weight spectrum. Drug and drug metabolite concentrations in dermal tissue are key in assessing local exposure and any toxicity related to the active agent. Based on our analysis, both animal models were shown to hold significant promise in LA product development.
KW - HIV prevention
KW - long-acting
KW - pre-exposure prophylaxis
KW - subdermal implant
KW - sustained release
KW - tenofovir alafenamide
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U2 - 10.3389/fphar.2020.569373
DO - 10.3389/fphar.2020.569373
M3 - Article
C2 - 33536904
AN - SCOPUS:85097412279
SN - 1663-9812
VL - 11
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 569373
ER -